CuCN-mediated cascade cyclization of 4-(2-bromophenyl)-2-butenoates: A high-yield synthesis of substituted naphthalene amino esters

Article abstract of DOI:10.1021/jo400244h

A new method of CuCN-mediated one-pot cyclization of 4-(2-bromophenyl)-2- butenoates leading to efficient synthesis of substituted naphthalene amino esters including phenanthrene aromatic structural units is described. Deuterium labeling studies establish

Full text of DOI:10.1021/jo400244h

Note
pubs.acs.org/joc
CuCN-Mediated Cascade Cyclization of 4‑(2-Bromophenyl)-2-
butenoates: A High-Yield Synthesis of Substituted Naphthalene
Amino Esters
R. Santhosh Reddy, Pragati K Prasad, Brij Bhushan Ahuja, and Arumugam Sudalai*
Chemical Engineering and Process Development Division, National Chemical Laboratory, Pashan Road, Pune 411 008, India
S
* Supporting Information
ABSTRACT: A new method of CuCN-mediated one-pot
cyclization of 4-(2-bromophenyl)-2-butenoates leading to
efficient synthesis of substituted naphthalene amino esters
including phenanthrene aromatic structural units is described.
Deuterium labeling studies establish that this one-pot cascade
cyclization proceeds through isomerization of olefin, intra-
molecular C−C bond cyclization, and aromatization as the key intermediates, all occurring in a single step.
150 °C, the corresponding ethyl 1-aminonaphthalene-2-
carboxylate 2a was isolated in 85% yield (Scheme 1).
ubstituted naphthalene amino esters are important building
1
Sblocks for the synthesis of pharmaceuticals and polycyclic
aromatic electronic materials.2 Conceptually, two strategies are
reported in the literature for their synthesis: (i) introduction of
functional groups onto a naphthalene nucleus and (ii) assembly
of naphthalene ring from benzene precursor. Evidently, the
annulation strategy is preferable since the availability of
functionalized naphthalene precursors is scarce and further
complicated by the fact that the reactive sites on a naphthalene
core are primarily governed by pre-existing functional group
orientations.3 Fortunately, many cyclization methods are
reported, that include annulations via Fischer carbenes,4a Pd-
catalyzed cyclization of alkynes with benzynes,4b−d addition of
α-lithio derivatives of 2-alkylbenzonitriles onto α,β-unsaturated
carboxylic acid derivatives,4e intramolecular cyclization of 4-(2-
cyanophenyl)-2-butenoic acid,4f [3 + 3] benzannulation of
benzenoid ring systems,5a reaction of 1-methoxybenzocyclobu-
tene with alkynes,5b TiCl4-mediated annulations of α-aryl-
substituted carbonyl compounds with alkynes,5c benzotriazole-
assisted aromatic ring annulations,5d Au-catalyzed annulations
with C−C triple bond,5e−i Pd-catalyzed sequential C−C bond
formation,5j−m and using nonmetallic processes.5n,o However,
the use of multiple reaction sequences, the expense of lithiated
reagents, considerably varying yields, and poor atom economy
are the major limitations often associated with these reports. In
continuation of our studies on the development of newer
synthetic methodologies,6 herein we report a novel CuCN-
mediated “one-pot” cascade cyclization that affords substituted
naphthalene amino esters directly from 4-(2-bromophenyl)-2-
butenoates.
Scheme 1. Synthesis of Ethyl 1-Aminonaphthalene-2-
carboxylate (2a)
For determining the optimal conditions (Table 1), substrate
1a was treated with CuCN (1 equiv) in DMF at 150 °C, which
gave the corresponding annulated product 2a in 28% yield. The
Table 1. CuCN-Mediated One-Pot Synthesis of Ethyl 1-
Aminonaphthalene-2-carboxylate 2a: Optimization Studies
a
temp
yield
b
entry
CN source (equiv)
CuCN (1)
(°C)
solvent
DMF
(%)
1
2
3
4
5
6
7
8
150
150
150
150
120
150
150
110
28
CuCN (2)
CuCN (3)
CuCN (3.5)
CuCN (3)
CuCN (3)
CuCN (3)
DMF
DMF
DMF
DMF
DMSO
DMAc
53
85
85
48
trace
25
c
d
NaCN (1.2) +
CuI (10 mol %)
toluene;
DMF
30 ; −
9
CuCN (1.3) + L-proline
120
DMF
49
a
Substrate 1a (1 mmol), CuCN (3 mmol), DMF (10 mL), 12 h.
b
c
Isolated yield after column chromatographic purification. Substitu-
The classical reaction of bromobenzene derivatives with
stoichiometric amount of CuCN in DMF at reflux temperature
(Rosenmund−von Braun reaction)7 invariably affords the
corresponding cyanobenzene derivatives.7 However, when the
same reaction was carried out with ethyl 4-(2-bromophenyl)-2-
butenoate 1a in the presence of CuCN (3 equiv) in DMF at
d
tion of Br with CN coupled with isomerized alkene was observed. No
reaction.
Received: February 17, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400244h | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1
yield of 2a was significantly improved to 53% when the CuCN
quantity was increased to 2 equivalents under the same reaction
conditions.
isomers in 1:1 mixtures of E/Z (determined from H NMR
analysis of their crude samples). However, acid hydrolysis of
4a−k afforded the corresponding phenyl acetaldehydes in good
yields, which were then immediately subjected to two-carbon
Wittig reaction (PPh3CHCO2Et, CH2Cl2) to afford 4-(2-
bromophenyl)-2-butenoates 1a−k in 84−93% yield (Scheme
2).
Interestingly, on further increasing the CuCN concentration
to 3 equiv, a dramatic improvement in the yield of 2a (85%)
was realized. However, lowering the temperature of the
reaction had a deleterious effect on the conversion. A brief
evaluation of solvents confirmed that DMF was the most
suitable one. In order to provide a catalytic process, we have
carried out the Cu-catalyzed reaction8 [CuI (10 mol %), KI,
DMEDA, NaCN] in toluene, which gave unexpectedly
cyanated product with isomerized alkene (30%). Further, use
of L-proline as an additive9 to minimize the CuCN quantity
gave 2a in moderate yield. After several experimentations, it was
thus found that a combination of o-bromo ester 1a (1 equiv)
and CuCN (3 equiv) in DMF at 150 °C for 12 h was the best
optimized conditions in achieving excellent product yields 2a−
k (Table 2).
When subjected to the CuCN-promoted cascade annulation
reaction with 3 equiv of CuCN, several 4-(2-bromophenyl)-2-
butenoates 1a−k gave the corresponding annulated substituted
naphthalene amino esters 2a−k in 73−91% yields. For instance,
substrates bearing halogen, alkyl, alkoxy, nitro, methylenedioxy
groups, etc. on the aromatic nucleus were well-tolerated under
the reaction conditions. Interestingly, electron-deficient sub-
strates gave higher yields of products as compared to electron-
rich substrates due to the mesomeric effect of electron-
withdrawing groups, thus increasing the electropositive
character of carbon in the CN group (Table 2).
It is found that the annulation is not merely restricted to the
synthesis of naphthalene derivatives 2a−j; it allows for the
synthesis of phenanthrene derivative (2k) as well (78% yield).
The formation of products 2a−k was confirmed from NMR,
HRMS, and X-ray crystallographic analysis (2h) (Supporting
Information).
Table 2. CuCN-Mediated One-Pot Synthesis of Substituted
Naphthalene Amino Esters
In order to gain insight into the mechanistic details of the
reaction, the following experiments were conducted: (a) when
α,β-unsaturated ester 5, 1b, or 6 was refluxed in DMF in the
absence of CuCN, the corresponding β,γ-unsaturated ester 7, 8,
or 9, respectively, in equilibrium with starting material 5, 1b, or
6 (ratio 3:2) was isolated; (b) additionally, when o-
bromoaromatic derivative 10 was subjected to CuCN-mediated
cyanation reaction, mere substitution of Br with CN took place
giving 11 without the isomerization of the CC bond
(Scheme 3). This observation suggests that, under thermal
conditions, the isomerization of CC bond might probably be
involved.11
substrates (1a−k)
a
entry
R1
R2
R3
R4
products (2a−k) yield (%)
a
b
c
d
e
f
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
85
78
74
73
76
81
88
91
82
86
78
OMe
OMe
H
H
H
OMe
OMe
OMe
Me
H
H
OMe
H
OBn
H
H
g
h
i
F
H
NO2
H
H
Scheme 3. Control Experiments
-O-CH2-O-
H
j
OMe
H
OMe
H
k
benzo fused
a
Isolated yield after column chromatographic purification.
Encouraged by the result, we became interested in
determining its scope by subjecting several 4-(2-bromophen-
yl)-2-butenoates 1a−k to the CuCN-promoted cascade
annulation. Several starting materials 1a−k were readily
prepared in three steps starting from o-bromobenzaldehydes
3a−k following a modified procedures.10 Thus, Wittig
olefination (MeOCH2PPh3Cl, KOtBu, THF) of 3a−k gave
the corresponding enol ethers 4a−k in 84−92% yield and
Scheme 2. Synthesis of 4-(2-Bromophenyl)-2-butenoates 1a−k
B
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The Journal of Organic Chemistry
Note
Scheme 4. Proposed Mechanism
from Sigma Aldrich, and 3b, 3c, 3d, 3e, 3h, 3i, 3j, and 3k were
synthesized by reported methods.13
To support this hypothesis, deuterium labeling experiments
were carried out as follows: when enolether 4c was hydrolyzed
with 2 N DCl and the product immediately subjected to Wittig
General Experimental Procedure for the Preparation of
Ethyl 4-(2-Bromophenyl)-2-butenoate Derivatives (1a−k). To a
stirred solution of (methoxymethyl)triphenylphosphonium chloride
(6.5 mmol) in THF (25 mL) was added KOtBu (5.75 mmol) at 0 °C.
The resulting mixture was stirred at the same temperature for 1 h. A
solution of 2-bromo aldehydes 3a−k (5.0 mmol) in THF (5 mL) was
added to the reaction mixture, and the resulting mixture was stirred at
room temperature. After 30 min, it was quenched with water and
diluted with EtOAc. The organic layer was separated, and the aqueous
layer was extracted with ethyl acetate (3 × 20 mL); the combined
organic layers were washed with brine (2 × 20 mL), dried over
anhydrous Na2SO4, and concentrated under reduced pressure to give
the crude product.
1
olefination, a mixture of 12 and 13 (3:2 ratio from H NMR
study) was obtained. This mixture on treatment with CuCN (3
equiv) in DMF resulted in the deuterated amino ester, i.e.,
deuterated compound 2c (73% yield), whose structure has
been established from deuterium NMR studies.12 In H NMR
1
spectrum of product 18 benzylic deuterium was not observed,
which confirms the isomerization via intermediate 14 in our
proposed mechanism. Based on this observation, a probable
mechanism is proposed in Scheme 4, in which a series of
transformations involving a isomerization of olefin (13 to 14),
intramolecular C−C bond cyclization (14 to 15), and
aromatization (15 to deuterium compound of 2c) are
presented as the key intermediates, all occurring sequentially
in a single step.
In conclusion, we have disclosed a simple annulation strategy
that affords a variety of substituted naphthalene amino esters
2a−k in high yields from the corresponding ethyl 4-(2-bromo-
phenyl)-2-butenoate derivatives 1a−k via CuCN-promoted
cyclization in a single step. Mechanistically, this annulation
involves isomerization of olefin, intramolecular C−C bond
cyclization, and aromatization as the key intermediates. We
believe that this one-pot cascade cyclization strategy will find
tremendous applications in the synthesis of bioactive molecules.
To a stirred solution of crude methyl vinyl ether derivatives 4a−k
(5.0 mmol) in THF (10 mL) was added an aqueous solution of 1 N aq
HCl (10 mL) at room temperature. The resulting solution was
refluxed for 3 h. After evaporation of the organic solvent in vacuo,
water was added to the mixture, and the resulting slurry was extracted
with EtOAc. The combined organic layers were washed with brine,
dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
obtained crude aldehydes were immediately used for the next reaction
without purification because of their instability to air and moisture.
To a stirred solution of the above crude aldehydes in CH2Cl2 (5
mL) at room temperature was added a Wittig reagent (5.5 mmol), and
the resulting mixture was stirred for 2 h at the same temperature. After
the completion of reaction, CH2Cl2 was distilled out to give the crude
product. Chromatographic purification of crude product [silica gel
(230−400 mesh) and petroleum ether/ethyl acetate (80:20) as eluent]
afforded the unsaturated esters 1a−k in pure form.
EXPERIMENTAL SECTION
■
Data Analysis for the Synthesis of New Compounds.14 (E)-
Ethyl 4-(2-Bromo-4,5-dimethoxyphenyl)but-2-enoate (1c).
Yield: 84% (1.38g, 4.192 mmol); colorless oil; IR (CHCl3, cm−1)
υmax 780, 936, 1032, 1071, 1156, 1176, 1239, 1280, 1468, 1712, 2978;
1H NMR (200 MHz, CDCl3) δ 1.28 (t, J = 7.2 Hz, 3H), 3.61 (dd, J =
1.6, 6.4 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.18 (q, J = 7.2 Hz, 2H),
5.76 (td, J = 1.5, 15.7 Hz, 1H), 6.81−7.13 (m, 3H); 13C NMR (50
MHz, CDCl3) δ 14.1, 38.1, 55.8, 60.0, 113.0, 114.2, 115.5, 122.4,
128.9, 146.7, 145.5, 148.4, 148.5, 166.0. Anal. Calcd for C14H17BrO4:
C, 51.08; H, 5.21; Br, 24.27. Found: C, 50.95; H, 5.13; Br, 24.34.
General Description. Solvents were purified and dried by
standard procedures before use; petroleum ether of boiling range
60−80 °C was used. Melting points are uncorrected and recorded on a
Buchi B-542 instrument. 1H NMR and 13C NMR spectra were
recorded on a Bruker AC-200 spectrometer unless mentioned
otherwise. Elemental analysis was carried out on a Carlo Erba
CHNS-O analyzer. Infrared spectra were recorded on Shimadzu FTIR-
8400 spectrometer, and absorption is expressed in cm−1. Purification
was done using column chromatography (230−400 mesh). Starting
materials 3a, 3f, and 3g are commercially available and were purchased
C
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Note
(E)-Ethyl 4-(2-Bromo-3,4-dimethoxyphenyl)but-2-enoate
(1d). Yield: 82% (1.35g, 4.101 mmol); colorless oil; IR (CHCl3,
cm−1) υmax 895, 978, 1024, 1050, 1142, 1188, 1245, 1276, 1477, 1714,
Na)+] 238.0844, found 238.0836. Anal. Calcd for C13H13NO2: C,
72.54; H, 6.09; N, 6.51. Found: C, 72.46; H, 6.24; N, 6.62.
Ethyl 1-Amino-6-methoxynaphthalene-2-carboxylate (2b).
Yield: 78% (0.191g, 0.778 mmol); gum; IR (CHCl3, cm−1) υmax 870,
1076, 1245, 1340, 1599, 1672, 3346, 3457; 1H NMR (200 MHz,
CDCl3) δ 1.42 (t, J = 7.1 Hz, 3H), 3.92 (s, 3H), 4.36 (q, J = 7.1 Hz,
2H), 6.97 (d, J = 8.8 Hz, 1H), 7.02−7.11 (m, 2H), 7.82 (t, J = 8.8 Hz,
2H); 13C NMR (50 MHz, CDCl3) δ 14.5, 55.2, 60.0, 103.2, 107.0,
115.1, 117.0, 117.9, 123.3, 127.5, 138.3, 148.9, 159.6, 168.8; HRMS
(ESI+) m/z calcd for (C14H15NO3)+ [(M + Na)+] 268.0950, found
268.0944. Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71.
Found: C, 68.44; H, 5.99; N, 5.49.
Ethyl 1-Amino-6,7-dimethoxynaphthalene-2-carboxylate
(2c). Yield: 74% (0.204g, 0.741 mmol); colorless oil; IR (CHCl3,
cm−1) υmax 798, 865, 964, 1015, 1135, 1157, 1232, 1264, 1471, 1665,
2965, 3335, 3346; 1H NMR (200 MHz, CDCl3) δ 1.42 (t, J = 7.1 Hz,
3H), 4.00 (s, 3H), 4.01 (s, 3H), 4.36 (q, 2H, J = 7.1 Hz), 6.95 (d, J =
8.9 Hz, 1H), 7.02 (s, 1H), 7.05 (s, 1H), 7.77 (d, 1H, J = 8.9 Hz); 13C
NMR (50 MHz, CDCl3) δ 14.4, 55.6 60.1, 101.1, 103.8, 107.1, 114.8,
117.6, 125.1, 132.4, 147.6, 148.6, 150.9, 168.8; HRMS (ESI+) m/z
calcd for (C15H17NO4)+ [(M + Na)+] 298.1055, found 298.1062. Anal.
Calcd for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.69; H,
6.18; N, 5.11.
1
2965; H NMR (200 MHz, CDCl3) δ 1.28 (t, J = 7.2 Hz, 3H), 3.61
(dd, J = 1.3, 7.1 Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.17 (q, J = 7.2
Hz, 2H), 6.81−7.27 (m, 3H); 13C NMR (50 MHz, CDCl3) δ 14.2,
38.1, 56.0, 60.1, 111.3, 120.3, 125.2, 130.2, 145.8, 146.7, 152.3, 166.2.
Anal. Calcd for C14H17BrO4: C, 51.08; H, 5.21; Br, 24.27. Found: C,
50.98; H, 5.14; Br, 24.32.
(E)-Ethyl 4-(5-(Benzyloxy)-2-bromo-4-methoxyphenyl)but-
2-enoate (1e). Yield: 84% (1.70g, 4.195 mmol); colorless oil; IR
(CHCl3, cm−1) υmax 780, 882, 1035, 1072, 1151, 1190, 1278, 1292,
1456, 1712, 2974; 1H NMR (200 MHz, CDCl3) δ 1.30 (t, J = 7.2 Hz,
3H), 3.27 (dd, J = 1.4, 7.1 Hz, 2H), 3.89 (s, 3H), 4.19 (q, J = 7.2 Hz,
2H), 5.10 (s, 2H), 6.14 (td, J = 7.2, 15.8 Hz, 1H), 7.02 (s, 2H), 7.32−
7.44 (m, 6H); 13C NMR (50 MHz, CDCl3) δ 14.1, 38.1, 55.8, 60.0,
113.0, 114.2,115.5, 122.4, 128.8, 145.5, 148.4, 166.0. Anal. Calcd for
C20H21BrO4: C, 59.27; H, 5.22; Br, 19.72. Found: C, 59.34; H, 5.28;
Br, 19.65.
(E)-Ethyl 4-(2-Bromo-4-nitrophenyl)but-2-enoate (1h). Yield:
84% (1.32g, 4.202 mmol); colorless oil; IR (CHCl3, cm−1) υmax 768,
1
878, 1018, 1085, 1178, 1285, 1298, 1455, 1716, 2960; H NMR (200
MHz, CDCl3) δ 1.27 (t, J = 7.2 Hz, 3H), 3.63 (dd, J = 1.3, 7.1 Hz,
2H), 4.16 (q, J = 7.2 Hz, 2H), 5.74 (td, J = 3.8, 15.7 Hz, 1H), 6.36 (dd,
J = 1.8, 2.9 Hz, 2H), 6.97−7.12 (m, 1H); 13C NMR (50 MHz, CDCl3)
δ 14.2, 38.1, 60.2, 98.0, 105.1, 106.8, 122.7, 139.1, 145.3, 156.9, 159.6,
166.2. Anal. Calcd for C12H12BrNO4: C, 45.88; H, 3.85; Br, 25.44; N,
4.46. Found: C, 45.76; H, 3.76; Br, 25.36; N, 4.39.
Ethyl 1-Amino-7,8-dimethoxynaphthalene-2-carboxylate
(2d). Yield: 73% (0.201g, 0.730 mmol); colorless oil; IR (CHCl3,
1
cm−1) υmax 779, 826, 956, 1018, 1267, 1579, 1672, 3334, 3464; H
NMR (200 MHz, CDCl3) δ 1.41 (t, J = 7.2 Hz, 3H), 3.97 (s, 6H), 4.35
(q, J = 7.2 Hz, 2H), 6.82 (d, J = 10.4 Hz, 1H), 7.24−7.28 (m, 1H),
7.41 (d, J = 9.0 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H); 13C NMR (50 MHz,
CDCl3) δ 14.5, 56.8, 61.5, 102.7, 114.1, 116.8, 118.0, 124.4, 125.3,
133.2, 147.0, 148.7, 151.1, 168.9; HRMS (ESI+) m/z calcd for
(C15H17NO4)+ [(M + Na)+] 298.1055, found 298.1049. Anal. Calcd
for C15H17NO4: C, 65.44; H, 6.22; N, 5.09. Found: C, 65.35; H, 6.31;
N, 5.12.
Ethyl 4-(2-Bromo-4,5-dimethoxyphenyl)pent-2-enoate (1j).
Yield: 89% (1.53g, 4.458 mmol); colorless oil; IR (CHCl3, cm−1) υmax
1
856, 937, 1030, 1133, 1233, 1268, 1445, 1716,2984; H NMR (200
MHz, CDCl3) δ 1.26 (t, J = 7.2 Hz, 3H), 1.37 (d, J = 7.0 Hz, 3H), 3.85
(s, 3H), 3.86 (s, 3H), 4.06 (qd, J = 5.5, 1.5 Hz, 1H), 4.19 (q, J = 7.2
Hz, 2H), 5.80 (dd, J = 15.79, 1.64 Hz, 1H), 6.63 (s, 1H), 7.01 (s, 1H),
7.09 (dd, J = 15.79, 5.69 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 14.1,
19.1, 40.1, 55.8, 60.0, 110.6, 113.9, 115.5, 120.4, 134.0, 148.2, 148.7,
150.9, 166.2 Anal. Calcd for C15H19BrO4: C, 52.49; H, 5.58; Br, 23.28.
Found: C, 52.33; H, 5.12; Br, 23.18.
Ethyl 4-(1-Bromonaphthalen-2-yl)but-2-enoate (1k). Yield:
89% (1.49g, 4.458 mmol); yellow oil; IR (CHCl3, cm−1) υmax 758, 872,
1058, 1175, 1184, 1245, 1468, 1713, 2962; 1H NMR (200 MHz,
CDCl3) δ 1.26 (t, J = 7.2 Hz, 3H), 3.89 (dd, J = 6.3, 1.6 Hz, 2H), 4.15
(q, J = 7.2 Hz, 2H), 5.77 (dt, J = 15.6, 1.6 Hz, 1H), 7.06−7.30 (m,
2H), 7.45−7.62 (m, 2H), 7.77 (t, J = 8.5 Hz, 2H), 8.30 (d, J = 8.3 Hz,
1H); 13C NMR (50 MHz, CDCl3) δ 14.3, 39.8, 60.2, 122.9, 124.4,
126.3, 127.4, 127.5, 127.8, 128.0, 128.3, 132.6, 133.5, 135.2, 145.2,
166.1. Anal. Calcd for C16H15BrO2: C, 60.21; H, 4.74; Br, 25.03.
Found: C, 60.11; H, 4.32; Br, 24.90.
General Experimental Procedure for the Preparation of
Substituted Naphthalene Derivatives (2a−k). To a stirred
solution of alkenes 1a−k (1 mmol) in dry DMF (10 mL) was
added CuCN (3 mmol,) and the entire solution was refluxed under N2
for 12 h (monitored by TLC). The reaction mixture was then cooled
to room temperature and diluted with water (20 mL) and EtOAc (15
mL). The organic layer was separated, and the aqueous layer was
extracted with EtOAc (3 × 20 mL). The combined organic extracts
were washed with brine, dried over anhydrous Na2SO4, and
concentrated under reduced pressure to give crude product, which
was purified by column chromatography [silica gel (230−400 mesh)
and petroleum ether/EtOAc (7:3) as an eluent] to give ethyl 1-amino-
2-naphthalene carboxylate derivatives (2a−k) in 73−91% yield.
Ethyl 1-Aminonaphthalene-2-carboxylate (2a). Yield: 85%
(0.183g, 0.850 mmol); gum; IR (CHCl3, cm−1) υmax 798, 865, 964,
1015, 1135, 1157, 1232, 1264, 1471, 1665, 2965, 3335, 3346; 1H NMR
(200 MHz, CDCl3) δ 1.42 (t, J = 7.1 Hz, 3H), 4.37 (q, J = 7.1 Hz,
2H), 7.05 (d, J = 8.9 Hz, 1H), 7.44−7.53 (m, 2H), 7.72 (d, J = 7.8 Hz,
1H), 7.87 (d, J = 8.9 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 14.4,
60.1, 104.2, 115.7, 121.4, 123.1, 125.0, 126.6, 128.2, 128.4, 136.4,
148.8, 168.8; HRMS (ESI+) m/z calcd for (C13H13NO2)+ [(M +
Ethyl 1-Amino-6-(benzyloxy)-7-methoxynaphthalene-2-car-
boxylate (2e). Yield: 76% (0.267 g, 0.759 mmol); colorless solid; mp
144−145 °C; IR (CHCl3, cm−1) υmax 1247, 1483, 1619, 1676, 3434,
3452; 1H NMR (200 MHz, CDCl3) δ 1.41 (t, J = 7.1 Hz, 3H), 4.00 (s,
3H), 4.35 (q, J = 7.1 Hz, 2H), 5.26 (s, 2H), 6.95 (d, J = 8.8 Hz, 1H),
7.04 (s, 1H), 7.18 (s, 1H), 7.30−7.51 (m, 5H), 7.76 (d, J = 8.8 Hz,
1H); 13C NMR (50 MHz, CDCl3) δ 14.5, 55.8, 60.1, 71.3, 104.3,
107.6, 115.2, 117.9, 125.5, 127.4, 128.1, 128.7, 132.9, 136.7, 147.5,
147.9, 151.8, 168.9; HRMS (ESI+) m/z calcd for (C21H21NO4)+ [(M
+ Na)+] 374.1368, found 374.1375. Anal. Calcd for C21H21NO4: C,
71.78; H, 6.02; N, 3.99. Found: C, 71.66; H, 5.94; N, 4.03.
Ethyl 1-Amino-6-methylnaphthalene-2-carboxylate (2f).
Yield: 81% (0.186g, 0.811 mmol); colorless oil; IR (CHCl3, cm−1)
1
υmax 1078, 1222, 1239, 1257 1605, 1663, 3352, 3453; H NMR (200
MHz, CDCl3) δ 1.43 (t, J = 7.1 Hz, 3H), 2.54 (s, 3H), 4.37 (q, J = 7.1
Hz, 2H), 7.02 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 8.2 Hz, 1H), 7.63 (d, J
= 8.1 Hz, 2H), 7.81 (d, J = 8.8 Hz, 1H); 13C NMR (50 MHz, CDCl3)
δ 14.5, 22.0, 60.2, 104.9, 116.1, 120.9, 123.4, 125.7, 128.4, 130.4, 134.6,
134.9, 147.9, 168.9; HRMS (ESI+) m/z calcd for (C14H15NO2)+ [(M
+ Na)+] 252.1000, found 252.0992. Anal. Calcd for C14H15NO2: C,
73.34; H, 6.59; N, 6.11. Found: C, 73.26; H, 6.52; N, 6.01.
Ethyl 1-Amino-6-fluoronaphthalene-2-carboxylate (2g).
Yield: 88% (0.205g, 0.870 mmol); gum; IR (CHCl3, cm−1) υmax
767, 1249, 1604, 1673, 2987, 3347, 3447; 1H NMR (200 MHz,
CDCl3) δ 1.43 (t, J = 7.2 Hz, 3H), 4.37 (q, J = 7.2 Hz, 2H), 6.99 (d, J
= 8.9 Hz, 1H), 7.15−7.24 (m, 1H), 7.34 (dd, J = 2.5, 7.1 Hz, 1H), 7.86
(d, J = 9.2 Hz, 1H), 7.9 (d, J = 8.9 Hz, 1H); 13C NMR (50 MHz,
CDCl3) δ 14.4, 60.2, 104.1, 111.8 (d, J = 20.8 Hz), 114.7 (d, J = 25.4
Hz), 115.1 (d, J = 3.9 Hz), 120.0, 124.2 (d, J = 10.0 Hz), 128.1, 138.0
(d, J = 9.2 Hz), 148.8, 162.2 (d, J = 249.7 Hz), 168.6; HRMS (ESI+)
m/z calcd for (C13H12FNO2)+ [(M + Na)+] 256.0750, found
256.0743. Anal. Calcd for C13H12FNO2: C, 66.94; H, 5.19; N, 6.01.
Found: C, 67.03; H, 5.13; N, 5.89.
Ethyl 1-Amino-6-nitronaphthalene-2-carboxylate (2h). Yield:
91% (0.237g, 0.911 mmol); Red solid; mp 176−177 °C; IR (CHCl3,
cm−1) υmax 1243, 1345, 1602, 1674, 3352, 3446; 1H NMR (200 MHz,
D
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Note
CDCl3) δ 1.45 (t, J = 7.0 Hz, 3H), 4.41 (q, J = 7.0 Hz, 2H), 6.90 (s,
2H), 7.23 (d, J = 8.8 Hz, 1H), 8.02 (t, J = 8.8 Hz, 1H), 8.18 (d, J = 2.3
Hz, 1H), 8.20 (d, J = 2.3, 1H), 8.65 (d, J = 2.0 Hz, 1H); 13C NMR (50
MHz, CDCl3) δ 14.4, 60.8, 107.2, 116.9, 118.3, 123.4, 124.5, 125.7,
129.1, 135.7, 147.1, 148.3, 168.2; HRMS (ESI+) m/z calcd for
(C13H12N2O4)+ [(M + Na)+] 283.0695, found 283.0687. Anal. Calcd
for C13H12N2O4: C, 60.00; H, 4.65; N, 10.76. Found: C, 59.95; H,
4.51; N, 10.65.
resulting mixture was stirred for the 2 h at the same temperature. After
the completion of the reaction, CH2Cl2 was distilled out to give the
crude product. Chromatographic purification of crude product [silica
gel (230−400 mesh) and petroleum ether/ethyl acetate (80:20) as
eluent] afforded the unsaturated esters 6 in pure form (1.7g, 0.6 mmol,
62% yield). Yield: 62% (1.7g, 0.6 mmol); colorless oil; IR (CHCl3,
cm−1) υmax 893, 964, 1051, 1142, 1163, 1241, 1263, 1456, 1712,2213,
1
2965; H NMR (200 MHz, CDCl3) δ 1.28 (t, J = 7.0 Hz, 3H), 3.57
Ethyl 5-Aminonaphtho[2,3-d][1,3]dioxole-6-carboxylate (2i).
Yield: 82% (0.213g, 0.822 mmol); gum; IR (CHCl3, cm−1) υmax 1243,
1345, 1602, 1674, 3352, 3446; 1H NMR (200 MHz, CDCl3) δ 1.41 (t,
3H, J = 7.0 Hz), 4.35 (q, J = 7.0 Hz, 2H), 6.05 (s, 2H), 6.90 (d, J = 8.8
Hz, 1H), 7.00 (s, 1H), 7.16 (s, 1H), 7.75 (d, J = 8.8 Hz, 1H); 13C
NMR (50 MHz, CDCl3) δ 14.4, 60.0, 98.7, 101.3, 104.5, 104.9, 115.6,
119.0, 125.5, 134.0, 147.4, 147.8, 149.2, 168.8; HRMS (ESI+) m/z
calcd for (C14H13NO4)+ [(M + Na)+] 282.0742, found 282.0747. Anal.
Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.79; H,
5.12; N, 5.46.
Ethyl 1-Amino-6,7-dimethoxy-5-methylnaphthalene-2-car-
boxylate (2j). Yield: 81% (0.234g, 0.809 mmol); yellow solid; mp
135−137 °C; IR (CHCl3, cm−1) υmax 798, 865, 964, 1063, 1205, 1232,
1250, 1462, 1482, 1513, 1602, 1674, 2980, 3352, 3471; 1H NMR (200
MHz, CDCl3) δ 1.43 (t, J = 7.1 Hz, 3H), 2.50 (s, 3H), 4.02 (s, 6H),
4.36 (q, J = 7.1 Hz, 2H), 7.11 (s, 1H), 7.13 (s, 1H), 7.61 (s, 1H); 13C
NMR (50 MHz, CDCl3) δ 14.3, 18.9, 55.3, 55.4, 59.8, 101.7, 103.5,
103.6, 118.1, 120.1, 124.8, 131.5, 146.3, 148.0, 150.5, 168.7; HRMS
(ESI+) m/z calcd for (C16H19NO4)+ [(M + Na)+] 312.1212, found
312.1217. Anal. Calcd for C16H19NO4: C, 66.42; H, 6.62; N, 4.84.
Found: C, 66.47; H, 6.48; N, 4.78.
(dd, J = 1.6, 6.3 Hz, 2H), 3.85 (s, 3H), 3.86 (s, 3H), 4.17 (q, J = 7.0
Hz, 2H), 5.74 (td, J = 1.6, 15.5 Hz, 1H), 6.86 (s, 1H), 7.01 (s 1H),
7.02 (td, J = 6.4, 15.5 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 14.2,
38.1, 56.0, 56.1, 60.9, 102.6, 107.3, 113.7, 118.0, 125.2, 129.1, 134.7,
148.7, 152.8, 171.1; HRMS (ESI+) m/z calcd for (C15H17NO4)+ [(M
+ Na)+] 298.1055, found 298.1049.
Experimental Procedure for the Preparation of (E)-Ethyl 4-
(3,4-Dimethoxyphenyl)but-3-enoate (7). (E)-Ethyl 4-(3,4-
dimethoxyphenyl)but-2-enoate 5 (0.25g, 1 mmol) was taken in dry
DMF (10 mL) and was heated at 150 °C under N2 for 12 h. The
reaction mixture was then cooled to room temperature and diluted
with water (30 mL) and EtOAc (25 mL). The organic layer was
separated, and the aqueous layer was extracted with EtOAc (3 × 20
mL). The combined organic extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated under reduced pressure to
give crude product that was purified by column chromatography [silica
gel (230−400 mesh) and petroleum ether/EtOAc (9:1) as an eluent]
to give (E)-ethyl 4-(3,4-dimethoxyphenyl)but-3-enoate 7 along with 5
(0.19g, 0.77 mmol, 89% yield). Yield: 89% (0.19g, 0.77 mmol);
colorless liquid; IR (CHCl3, cm−1) υmax 882, 978, 1045, 1148, 1175,
1
1248, 1275, 1390, 1412, 1718, 2890; H NMR (200 MHz, CDCl3) δ
Ethyl 1-Aminophenanthrene-2-carboxylate (2k). Yield: 71%
(0.188g, 0.709 mmol); yellow oil; IR (CHCl3, cm−1) υmax 791, 845,
964, 1052, 1215, 1239, 1240, 1412, 1472, 1533, 1664, 2970, 3332,
3451; 1H NMR (200 MHz, CDCl3) δ 1.44 (t, J = 7.1 Hz, 3H), 4.40 (q,
J = 7.1 Hz, 2H), 7.11 (d, J = 8.6, 1H), 7.49−7.64 (m, 3H), 7.73 (d, J =
8.7, 1H), 7.88 (dd, J = 9.0, 1.6, 1H), 8.05 (d, J = 8.5, 1H), 9.19 (d, J =
8.2, 1H); 13C NMR (50 MHz, CDCl3) δ 14.4, 60.4, 108.2, 116.7,
119.1, 124.5, 125.6, 126.5, 127.0, 128.3, 129.1, 129.6, 130.8, 132.8,
137.1, 151.0, 169.1; HRMS (ESI+) m/z calcd for (C17H15NO2)+ [(M
+ Na)+] 288.1000, found 288.1009. Anal. Calcd for C17H15NO2: C,
76.96; H, 5.70; N, 5.28. Found: C, 76.71; H, 5.51; N, 5.22.
(E)-Ethyl 4-(3,4-Dimethoxyphenyl)but-2-enoate (5). IR
(CHCl3, cm−1) υmax 856, 965, 1054, 1144, 1163, 1241, 1263, 1312,
1456, 1714, 2864; 1H NMR (200 MHz, CDCl3) δ 1.28 (t, J = 7.2 Hz,
3H), 3.45 (dd, J = 1.5, 6.6, Hz, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 4.18
(q, J = 7.2 Hz, 2H), 5.78 (td, J = 1.6, 15.5 Hz, 1H), 6.65−6.72 (m,
2H), 6.78−6.82 (m, 1H), 7.06 (td, J = 6.6 15.5 Hz, 1H); 13C NMR
(50 MHz, CDCl3) δ 14.0, 37.8, 55.5, 55.6, 59.9, 111.2, 111.7, 120.6,
121.8, 129.8, 147.3, 147.6, 148.8, 166.1; HRMS (ESI+) m/z calcd for
(C14H18O4)+ [(M + Na)+] 273.1103, found 273.1108.
Experimental Procedure for the Preparation of (E)-Ethyl 4-
(2-Cyano-4,5-dimethoxyphenyl)but-2-enoate (6). Potassium
osmate dehydrate (36 mg, 0.1 mmol) and N-methylmorpholine N-
oxide (2.3g, 20 mmol) were added to a solution of 2-allyl-4,5-
dimethoxybenzonitrile (2.03g, 10 mmol) in acetone/H2O (30 mL, 1:1
ratio) and stirred at room temperature until all of the starting material
had been consumed by TLC (12 h). CH2Cl2 was added, and the
aqueous layer was extracted with CH2Cl2 (3 × 10 mL). Organic
extracts combined, dried over anhydrous Na2SO4, and concentrated to
give the crude diol, which was then directly taken for the next step
without purification.
1.29 (t, J = 7.2 Hz, 3H), 3.21 (dd, J = 1.3, 7.1, Hz, 2H), 3.87 (s, 3H),
3.90 (s, 3H), 4.17 (q, J = 7.2 Hz, 2H), 6.07−6.25 (m, 1H), 6.33−6.46
(m, 1H), 6.76−6.80 (m, 1H), 6.85−6.92 (m, 2H); HRMS (ESI+) m/z
calcd for (C14H18O4)+ [(M + Na)+] 273.1103, found 273.1107.
Experimental Procedure for the Preparation of (E)-Ethyl 4-
(2-Bromo-4,5-dimethoxyphenyl)but-3-enoate (8). Same as
described for compound 7. Yield: 87% (0.285g, 0.870 mmol);
colorless liquid; IR (CHCl3, cm−1) υmax 893, 964, 1051, 1142, 1163,
1241, 1263, 1456, 1712, 2965; 1H NMR (200 MHz, CDCl3) δ 1.31 (t,
J = 7.0 Hz, 3H), 3.31 (dd, J = 1.3,5.6 Hz, 2H), 3.90 (s, 6H), 4.20 (q, J
= 7.0 Hz, 2H), 5.74 (td, J = 7.0, 15.7 Hz, 1H), 6.78 (td, J = 1.2, 15.7
Hz, 1H), 6.98 (s 1H), 7.05 (s, 1H); HRMS (ESI+) m/z calcd for
(C14H17BrO4)+ [(M + Na)+] 351.0208, found 351.0214.
Experimental Procedure for the Preparation of (E)-Ethyl 4-
(2-Cyano-4,5-dimethoxyphenyl)but-3-enoate (9). Same as de-
scribed for compound 7. Yield: 83% (0.198g, 0.689 mmol); colorless
oil; IR (CHCl3, cm−1) υmax 848, 1092, 1219, 1268, 1485, 1514, 2212,
1
1714, 2961; H NMR (200 MHz, CDCl3) δ 1.31 (t, J = 7.0 Hz, 3H),
3.31 (dd, J = 7.0, 1.4 Hz, 2H), 3.90 (s, 3H), 3.96 (s, 3H), 4.20 (q, J =
7.0 Hz, 2H), 6.40 (td, J = 15.8, 7.0 Hz,1H), 6.78 (d, J = 15.8 Hz, 1H),
6.98 (s, 1H), 7.05 (s, 1H); 13C NMR (50 MHz, CDCl3) of compound
9 + compound 6 δ 14.2, 36.4, 38.1, 56.1, 60.3, 60.8, 102.6, 103.8,
107.3, 112.2, 113.6, 114.2, 117.9, 123.8, 125.2, 129.0, 134.6, 135.7,
144.6, 148.1, 148.7, 152.7, 165.8, 170.9. HRMS (ESI+) m/z calcd for
(C15H17NO4)+ [(M + Na)+] 298.1055, found 298.1051.
Experimental Procedure for the Preparation of 2-((E)-3-
Cyanoallyl)-4,5-dimethoxybenzonitrile (11). Same as described
for compound 7. Yield: 71% (0.199g, 0.71 mmol); colorless oil; IR
(CHCl3, cm−1) υmax 1031, 1164, 1218, 1381, 1440, 1506, 2218, 2840,
2932, 3008; 1H NMR (200 MHz, CDCl3) δ 3.89 (s, 3H), 3.90 (d, J =
11.3 Hz, 2H), 3.93 (s, 3H), 5.48 (d, J = 10.8 Hz, 1H), 6.65 (td, J = 7.5,
10.8 Hz, 1H), 6.80 (s, 1H), 7.04 (s, 1H); 13C NMR (50 MHz, CDCl3)
δ 36.1, 56.1, 56.2, 101.4, 103.5, 112.3, 114.2, 115.5, 117.7, 135.0, 148.4,
150.3, 153.2; HRMS (ESI+) m/z calcd for (C13H12N2O2)+ [(M +
Na)+] 251.0796, found 251.0791.
To a vigorously stirred suspension of silica gel-supported NaIO4
reagent (2.1g, 10 mmol) in CH2Cl2 was added a solution of the crude
vicinal diol in CH2Cl2. The reaction was monitored by TLC until
disappearance of the starting material. The mixture was filtered
through a sintered glass funnel, and the silica gel was thoroughly
washed with CH2Cl2. The organic extract was washed with brine and
dried over anhydrous Na2SO4, and the crude aldehyde was used
immediately in the Wittig reaction.
Experimental Procedure for the Preparation of Compound
13. To a stirred solution of 1-bromo-4,5-dimethoxy-2-((E)-2-
methoxyvinyl)benzene 4c (1.3g, 5.0 mmol) in THF (10 mL) was
added 1 N DCl/D2O (2 mL) at room temperature. The resulting
solution was heated at 150 °C for 3 h. After evaporation of the organic
solvent in vacuo, EtOAc was added to the mixture, and acid was
To a stirred solution of above crude aldehyde in CH2Cl2 at room
temperature was added Wittig reagent (3.8g, 11.1 mmol), and the
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The Journal of Organic Chemistry
Note
neutralize by adding NaHCO3. The organic layer was separated, dried
over anhydrous Na2SO4, filtered, and concentrated in vacuo. The
obtained crude aldehydes were immediately used for the next reaction
without purification because of their instability to air and moisture. To
a stirred solution of the above crude aldehydes in CH2Cl2 (5 mL) at
room temperature was added a Wittig reagent (1.9g, 5.5 mmol), and
the resulting mixture was stirred for 2 h at the same temperature. After
the completion of reaction, CH2Cl2 was distilled out to give the crude
product. Chromatographic purification of crude product [silica gel
(230−400 mesh) and petroleum ether/ethyl acetate (80:20) as eluent]
afforded the deuterated unsaturated esters 13 in pure form (0.271g,
0.81 mmol, 82%). Yield: 82% (0.271g, 0.81 mmol); colorless oil; IR
(CHCl3, cm−1) υmax 895, 978, 1024, 1050, 1142, 1188, 1245, 1276,
1477, 1714, 2965; 1H NMR (200 MHz, CDCl3) δ 1.28 (t, J = 7.0 Hz,
3H), 3.48 (d, J = 1.3, 6.4 Hz, 0.42H), 3.85 (s, 3H), 3.86 (s, 3H), 4.18
(q, J = 7.0 Hz, 2H), 5.74 (d, J = 15.6 Hz, 0.38 H), 6.66 (s, 1H), 6.98
(d, 15.6 Hz, 1H), 7.01 (s, 1H); 13C NMR (50 MHz, CDCl3) δ 14.3,
34.0, 34.2, 34.4, 34.6, 34.8, 55.9, 56.1, 59.9, 113.4, 114.0, 115.5, 119.7,
119.9, 120.2, 130.9, 146.5, 146.7, 148.3, 148.6, 166.2; HRMS (ESI+)
m/z calcd for (C14H15D2BrNO4)+ [(M + Na)+] 353.0333, found
353.0337.
Experimental Procedure for the Preparation of Deuterated
Compound 2c. The deuterated (E)-ethyl 4-(2-bromo-4,5-
dimethoxyphenyl)but-2-enoate 13 (1 mmol) was taken in dry DMF
(10 mL), CuCN (3 mmol) was added to it, and the entire solution was
refluxed under N2 atmosphere for 12 h. The reaction mixture was then
cooled to room temperature, the 2H NMR spectrum was recorded for
crude product in DMF, and the presence of dideuterium on nitrogen
(ND2) in product 2c was observed. The product deuterated
compound of 2c was further confirmed by comparing the deuterium
NMR spectrum of deuterated product 2c in DMF. It is notable that
the benzylic deuterium was not observed in the 1H NMR spectrum of
product 2c, which confirms the isomerization in our proposed
mechanism.
Takada, K.; Tanaka, H.; Kitamura, T.; Morikawa, O.; Konishi, H. J.
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A. R.; Reddy, R. S.; Sudalai, A. Org. Lett. 2009, 4, 803−805. (c) Reddy,
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2232.
ASSOCIATED CONTENT
■
(12) The 2H NMR spectrum of the crude mixture in DMF confirmed
the formation of 16 with dideuterium on nitrogen (ND2). The product
S
* Supporting Information
Copies of 1H NMR and 13C NMR spectra for all new
substances and X-ray crystallographic data for 2h. This material
is available free of charge via the Internet at http://pubs.acs.org.
2
16 was further confirmed by comparing the H NMR spectrum of
deuterated product 2a in DMF.
(13) (a) Moleele, S. S.; Michael, J. P.; Koning, C. B. Tetrahedron
2006, 62, 2831−2844. (b) Roberto Olivera, R.; SanMartin, R.;
Domínguez, E.; Solans, X.; Urtiaga, M. K.; Arriortua, M. I. J. Org.
Chem. 2000, 65, 6398−6411. (c) Dubost, E.; Fossey, C.; Cailly, T.;
Rault, S.; Fabis, F. J. Org. Chem. 2011, 76, 6414−6420.
(14) (a) Suzuki, Y.; Nemoto, T.; Kakugawa, K.; Hamajima, A.;
Hamada, Y. Org. Lett. 2012, 14, 2350−2353.
AUTHOR INFORMATION
Corresponding Author
*E-mail: a.sudalai@ncl.res.in.
■
Notes
The authors declare no competing financial interest.
REFERENCES
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